PROJECT SUMMARY/ABSTRACT The pathogenic pathways involved in Alzheimer's disease (AD) involve ?-amyloid (A?)- containing plaques and neurofibrillary tangles (NFTs) composed of phosphorylated tau protein. With only temporary, symptomatic treatments for AD available, effective disease-modifying intervention is desperately needed. The availability of protein signatures of AD may improve clinical trial design and analysis, increasing the likelihood of successful drug development by a better understanding and characterization of patients in trials. CNS derived exosomes may be a source of proteins that signal the progress of the disease. The precise mechanisms of exosome production and trafficking in AD are not understood, although the Rissman group and others have demonstrated the utility of exosomes as biomarkers and for prediction of treatment effects in human plasma. In this proposal, Drs. Rissman and Yates will use these unique resources to advance the understanding of exosome contents and trafficking to advance the field of AD diagnosis.